2,3-epithio-5alpha-androst-6-ene compounds

ABSTRACT

2A,3A - EPITHIO - 17-OXYGENATED-5A-ANDROST-6-ENE COMPOUNDS OF THE FORMULA:   2,3-(-S-),17(X=)ANDROST-6-ENE   WHEREIN X IS AN OXO GROUP OR A   (R&#39;&#39;-),(R-O--)   GROUP, IN WHICH R IS A HYDROGEN ATOM OR AN OPTICALLY SUBSTITUTED LOWER HYDROCARBON-CARBONYL GROUP OR A SUBSTITUTED OR UNSUBSTITUTED CYCLO-LOWER HYDROCARBON GROUP OR TETRAHYDROPYRANYL GROUP OR TETRAHYDROFURANYL GROUP; R&#39;&#39; IS A HYDROGEN ATOM OR A LOWER HYDROCARBON GROUP, HAVING STRONG ANTIESTROGENIC ACTIVITY ACCOMPANIED WITH LEAST SIDE EFFECTS PHARMACEUTICAL PREPARATION CONTAINING ONE OR MORE OF THEM AND PROCESS FOR PREPARATION OF THESE COMPOUNDS.

United States Patent 015 3,749,778 2,3-EPlTHIO-5a-ANDROST-6-ENE COMPOUNDS Taichiro Komeno, Osaka, Japan, assiguor to Shionogi 8: Co., Ltd., Higashi-ku, Osaka, Japan No Drawing. Application Dec. 24, 1969, Ser. No. 888,031,

which is a continuation-impart of abandoned application Ser. No. 769,412, Oct. 21, 1968. Divided and this application Aug. 30, 1971, Ser. No. 176,279

Claims priority, application Japan, Oct. 25, 1967, 42/68,682 Int. Cl. A61k 17/00 US. Cl. 424-241 25 Claims ABSTRACT OF THE DISCLOSURE 211,30: epithio 17-oxygenated-Sa-androst-6ene compounds of the formula:

SI i

wherein X is an oxo group or a group, in which R is a hydrogen atom or an optionally substituted lower hydrocarbon-carbonyl group or a substituted or unsubstituted cyclo-lower hydrocarbon group or tetrahydropyranyl group or tetrahydrofuranyl group; R is a hydrogen atom or a lower hydrocarbon group, having strong antiestrogenic activity accompanied with least side eifects, pharmaceutical preparation containing one or more of them and process for preparation of these compounds.

wherein X is an oxo group or a group, in which R is a hydrogen atom or an optionally substituted lower hydrocarbou-carboxylic acyl group or a substituted or unsubstituted cyclo-lower hydrocarbon group or tetrahydropyranyl group or tetrahydrofuranyl 3,74%,778 Patented July 31, 1973 group; R is a hydrogen atom or a lower hydrocarbon group.

The parent compounds lacking a double bond at position 6, namely 2a,3a-epithiO-Sa-andmstane compounds have been utilized as most potential anabolic and antiestrogenic agent. However, they still possessed about a half of androgenic activity of testosterone. Therefore, when the compounds are administered to a female, or when the androgenic effect is undesirable,-side effects such as virilism, etc., were serious problems to be solved for clinical use. In contrast, the compounds of the present invention have stronger antiestrogenic activity and related activities in contrast to one twentieth myogenic and one tenth androgenic activities than the parent compounds. and are the best antiestrogenic substances of the hitherto developed compounds. This feature is of the greatest importance in actual application, and the compounds of the present invention almost completely solved the ditficult problems. Thus the compounds of the present invention are the best known medicines for treatment of masthopatia, gynecomastia, alleviation of symptom of mammary tumor and treatment of other diseases demanding antiestrogenic agent, with least side efiects.

The compounds of the present invention are 2a,3aepithio 5ot-androst-6-en-17/3-ol and its modifications at position 17. The substituent at position represented by R may be a hydrogen atom or a lower hydrocarbon group. Such a hydrocarbon group involves methyl, ethyl, propyl, isobutyl, vinyl, ethynyl, propinyl group and the like containing up to four carbon atoms. The hydroxyl group at position 17 8 may be acylated or etherized. The acylates or ethers represented by R0 may be substituted or unsubstituted aliphatic acylates for example, alkanoates e.g. formate, acetate, propionate, enanthate, octanoate, decanoate, trimethylacetate, tert-butylacetate, cycloalkylalkanoates, adamantoate, haloacetate, crotonate, succinate, glutamate, camphorate, phenylpropionate, and the like, or aromatic acylates for example substituted or unsubstituted benzoate, e.g. sulfobenzoate, furoate, nicotinate, phthalate, substituted or unsubstituted phenoxyacetates, etc., or ethers for example substituted or unsubstituted tetrahydropyranyl ether, tetrahydrofuranyl ether, l-cycloalkenyl ether, l-alkoxycyloalkyl ether and the like.

Typical examples of the compounds of the present invention include: 2u,3u-epithio-5a-androst-6-en-17-one, 2oz, 3a epithio 5a-androst-6-en-l7fl-ol, 2u,3a-epithio-5a-androst-6-en-l7B-ol lower alkanoate, e.g. acetate, propionate, enanthate, octanoate, decanoate, etc., 2a,3u-epithio-5aandrost 6-en-17fl-ol phenylpropionate, 20,3ot-6PiihiO-5ot-3Ildrost-6-en-17fi-ol benzoate, 20,3a-epithiO-Ua-methyl-Saandrost 6-en-17 8-ol, 2a,3a-epithio-l7a-ethyl-5ot-androst- 6 en 17,8-01, 2u,3a-epithio-17a-ethynyl-5a-androst-6- en -01, 2a,3a-epithio-Su-androst=6-en-175-01 tetrahydropyranyl ether, 2a,3a-epithio-17,B-(l-lower alkoxycycloalkyl)oxy 50c androst-6-ene e.g. 2a,3a-epithio-17B-(lmethoxycyclopentyl)oxy-5a-androst-6-ene, and the like.

The compounds can be prepared from the known compounds by various methods. For example, 3,17-diacetyloxyandrost-S-ene is oxidized with chromium trioxide to obtain 7-oxoandrost-5-ene compound, which is hydrogenated, brominated at position 6, reduced at the ketone group at position 7 to afford bromohydrin and then dehydroxybrominated to introduce a double bond at position 6 and then oxidized at 3/3-hydroxyl group to obtain 3-oxo-5a-androst-6-en-175-01. The novel compound thus obtained is halogenated at position 2 with a halogenating agent avoiding halogenation of the double bond at position 6, treated with a reducing agent to obtain novel 3,8-hydroxy-2u-halo-5a-androst-6-ene compounds, and finally treated with a basic compound to obtain novel 25,3/3-epoxy-17-oXygenated-5ot-androst-6-ene compounds,

the starting material of the present invention. If required, modification at position 17 may be effected by e.g. oxidation of 17-hydroxyl group to l7-oxo group followed by reaction with an organo-metallic compound to give Nix-hydrocarbon substituted derivatives, or esterification or etherification at 17-hydroxyl group to obtain 17-ester or 17-ether.

The 2fi,3fi-epoxy-17-oxygenated-5a-androst-6-ene compounds are treated with thiocyanic acid in ether to give 3a-thiocyanato-5a-androst-6ene-2 3-ol compounds, which are then treated in a basic medium to obtain the desired 2a,3ot-epithio-5a-androst-6-ene compounds. The products are acylated or etherified when necessary, according to conventional methods, e.g., by treatment with acid anhydried or acid halide, or treatment with 1,1-di1ower all oxycycloalkane.

The compounds of the present invention represented by the general Formula I have valuable pharmacological activities. For example, they are useful agents for regulation of physiological functions as evidenced by their antiestrogenic activity, myogenic activity, androgenic activity, uterotropic activity or antiuterotropic activity, antimammary growth activity, implantation delay and related activities. They are characterized by increase in the ratio of the major activities, namely antiestrogenic activity to myogenic and androgenic activities. For example, oral administration of 0.5 mg. of 2a,3a-epithio-5aandrost-6-en-l7/3-ol 17-acetate or subcutaneous administration of 0.3 mg. of 2a,3a-epithio-5u-androst-6-en-175-01 per a mouse inhibited 48% or 56% of effect of simultaneously administered estradiol when estimated on vaginal TIC reduction. Subcutaneous injection of 10 mg. 204,3wepithio-a-androst-6-en-17B-ol per a rat showed about the same increase in weight of seminal vesicle and about a half of the increase in weight of levator ani muscle when compared with that of 1 mg. testosterone propionate. These values show that the compounds of the present invention have stronger antiestrogenic activity than 2a,3a-epithio-5ot-androstane compounds in spite of one twentieth myogenic activity and one tenth androgenic activity. Thus the compounds of the present invention are excellent medicines for treatment of masthopatia, gynecomastia, alleviation of symptoms of mammary tumor and treatments of diseases demanding antiestrogenic agents with least side effects for human and veterinary medicaments or additives to baits in a manner per se conventional in the art at a dose of 17 to 100 mg. per kilogram of body weight for a day.

The compounds may be utilized in a wide variety of oral or parenteral dosage forms, solely or in admixture with other co-acting substances. They may be administered with a pharmaceutical carrier which can be a solid material or a liquid material in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, granules, capsules, pills or the like. The liquid composition may take the form of injections, ointments, dispersions, suspensions, solutions, emulsions, syrups or elixirs. They may be flavoured, colored, and tablets and granules may be coated. All of the diluents e.g. starch, sucrose, lactose, calcium carbonate, kaolin, etc., coloring agents, aromatic substances, flavouring substances, bulking agents e.g. lactose, salt, glycine, starch, calcium carbonate, kaolin, bentonite, calcium phosphate, etc., binders e.g. starch, acacia, gelatin, glucose, sodium alginate, tragacanth, carboxymethylcellulose, etc., disintegrators e.g. starch, agar, carbonates, etc., lubricants e.g. stearic acid, talc, paraffin, boric acid, sodium benzoate, Carbowax, cacao oil, etc., ointment bases e.g. fats, oils, lard, wool fat, vaselin, glycerin, resins, glycols, emulsifying agents, etc., solvents e.g. water, polyethyleneglycol, olive oil, peanut oil, sesame oil, cacao oil, methyl or ethyl oleate, etc., solubilizing agent, buffers and stabilizing agents, may be used if the agents do not exert wrong effect on the compounds.

The following examples are given by way of illustration only and are not intended as limitations of the present invention, many apparent variations of which are possible without departing from the spirit and scope thereof. The abbreviations have the conventional meanings.

EXAMPLE 1 A solution in oil for intramuscular injection composed of 10 mg. of 2a,3a-epithio-5a-androst-6-en-175-01 in 1 ml. of anhydrous sesame oil is prepared by sterilized procedure and administered once or twice a week to a patient, e.g. a woman in breast tumor.

EXAMPLE 2 An injection for subcutaneous injection, composed of 15 mg. of 2a,3u-epithio-5a-androst-6-en-l7fi-ol in 2 ml. of buffer solution is prepared by a conventional method and administered once a week to a patient, e.g. a man in gynecomastia.

EXAMPLE 3 Ten tablets are prepared from 25 mg. 2a,3a-epithio-l7amethyl-5a-androst-6-en-17,8-01, 750 mg. lactose, 220 mg. corn starch, 30 mg. magnesium stearate and 1.9 g. sucrose, using gum arabic, talc, distilled water, coloring agent and then coated with sugar syrup, gum arabic and talc. Four tablets are administered to a patient per a day, e.g. a woman in mastopathia.

What We claim is:

1. A pharmaceutical preparation for human and veterinary use comprising an effective amount of a compound of the formula:

wherein X is 0x0 or a group wherein X is 0x0 or a group R! in which R is hydrogen, optionally substituted lower bydrocarbon-carboxylic acyl, optionally substituted cyclolower hydrocarbon group, tetrahydropyranyl, or tetrahydrofuranyl group, and R is hydrogen or lower hydrocarhon group.

4. A pharmaceutical preparation according to claim 1, wherein the effective compound is 2a,3a-epithio-5a-androst-6-ene-17B-ol.

5. A pharmaceutical preparation according to claim 1, wherein the effective compound is 2a,;3a-epithio 17a-n1ethyl-S ot-andro st-6-ene- 17,8-01.

6. A pharmaceutical preparation according to claim 1, wherein the effective compound is 211,306-6Plt1'1lO-50t-311- drost-6-ene-l7-one.

7. A pharmaceutical preparation according to claim 1, wherein the effective compound is 2u,3a-epithio-5-androst-6-ene-l7B-ol lower alkanoate.

8. A pharmaceutical preparation according to claim 1, wherein the eifective compound is 20,3oc-6plllhl0-5OL-aI1- drost-6-en-17,8-ol enanthate.

9. A pharmaceutical preparation according to claim 1, wherein the effective compound is 2a,3a-epithio-5a-androst-6-en-17B-ol octanoate.

10. A pharmaceutical preparation according to claim 1, wherein the eifective compound is 2a,3u-epithio-5a-androst-6-en-17B-ol decanoate.

11. A pharmaceutical preparation according to claim 1, wherein the eflective compound is 2a,3a-epithio-5a-androst-6-en-17,8-ol benzoate.

12. A pharmaceutical preparation according to claim 1, wherein the effective compound is 2a,3a-epithio-5a-androst-6-en-17fl-ol phenylpropionate.

13. A pharmaceutical preparation according to claim 1, wherein the eifective compound is 2a,3a-epithio-l7a-ethyny1-5a-androst-6-en-l7fi-ol.

14. A pharmaceutical preparation according to claim 1, wherein the effective compound is 20:,30c-6Plthi0-17B-(1- methoxycyclop en tyl oxy-S u-androst-6-ene.

15. A process according to claim 3, wherein the effective compound is 2a,3u-epithiO-Sa-androst-6-ene-17,8- 01.

16. A process according to claim 3, wherein the effective compound is 2u,3u-epithio-17a-methyl-5ot-androst-6- ene-17fl-ol.

17. A process according to claim 3, wherein the effective compound is 2a,3a-epithio-5a-androst-6-ene-l7-one.

18. A process according to claim 3, wherein the efiective compound is 20,3u epithio-5-androst-6-ene-17,8-01 lower alkanoate.

19. A process according to claim 3, wherein the effective compound is 2a,3a-epithio-5u-androst-6-en-17,8-01 enanthate.

20. A process according to claim 3, wherein the effective compound is 2a,3ot-epithio-5a-androst-6-en-17,8-ol octanoate.

21. A process according to claim 3, wherein the effective compound is 2a,3a epithio-5ot-androst-6-en-17,8-01 decanoate.

22. A process according to claim 3, wherein the effective compound is 2a,3a epithio-5a-androst-6-en-17,8-01 benzoate.

23. A process according to claim 3, wherein the eifective compound is 2a,3a-epithio-5a-androst-6-en-1718-01 phenylpropionate.

24. A process according to claim 3, wherein the effective compound is 2a,3a epithio-17a-ethynyl-5a-androst-6-en- -01.

25. A process according to claim 3, wherein the effective compound is 2a,3ot-epithio-17,8-(l-methoxycyclopentyl oxy-S a-andro st-6-ene.

References Cited UNITED STATES PATENTS 3,230,215 1/1966 Komeno 260-2395 3,290,294 12/1966 Komeno 260-239.5 3,301,850 1/1967 Klimstra 260239.5 3,405,124 10/1968 Klimstra 260239.5 3,519,715 7/1970 Nagata et al. 42424l SHEP K. ROSE, Primary Examiner U.S. Cl. X.R. 260-239.5 

